Methods of treatment with drug delivery after biodegradation of the stent scaffolding

ABSTRACT

Disclosed is a stent comprising a bioabsorbable polymeric scaffolding; and a plurality of depots in at least a portion of the scaffolding, wherein the plurality of depots comprise a bioabsorbable material, wherein the degradation rate of all or substantially all of the bioabsorbable polymer of the scaffolding is faster than the degradation rate of all or substantially all of the bioabsorbable material of the depots.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.13/925,750 filed Jun. 24, 2013 which is a continuation of U.S.application Ser. No. 13/185,370 filed Jul. 18, 2011 which is a divisionof U.S. application Ser. No. 11/823,703, filed on Jun. 27, 2007 andpublished on Feb. 28, 2008 as U.S. Patent Application Publication No.2008-0051880 A1, and issued on Sep. 13, 2011, as U.S. Pat. No.8,016,879, which claims the benefit of U.S. Provisional PatentApplication No. 60/834,885, filed on Aug. 1, 2006, and U.S. applicationSer. No. 11/823,703 is also a continuation in part of U.S. applicationSer. No. 11/582,706, filed on Oct. 17, 2006 and published on Apr. 17,2008 as U.S. Patent Application Publication No. 2008-0091262 A1. All ofthese applications are incorporated by reference herein in theirentirety, including any drawings.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a stent for treating a disorder witha drug over a period of time extending beyond biodegradation of thestent scaffolding.

2. Description of the Background

In particular, the invention relates to radially expandableendoprostheses that are adapted to be implanted in a body lumen. An“endoprosthesis” corresponds to an artificial device that is placedinside the body. A “lumen” refers to a cavity of a tubular organ such asa body lumen. A stent is an example of such an endoprosthesis. Stentsare generally cylindrically shaped devices which function to hold openand sometimes expand a segment of a body lumen or other anatomical lumensuch as urinary tracts and bile ducts. Stents are often used in thetreatment of atherosclerotic stenosis in body lumens. “Stenosis” refersto a narrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty. “Restenosis” refers to thereoccurrence of stenosis in a body lumen or heart valve after it hasbeen subjected to angioplasty or valvuloplasty.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a body lumen to the treatment area ina body lumen. “Deployment” corresponds to the expanding of the stentwithin the lumen at the treatment area. Delivery and deployment of astent are accomplished by positioning the stent at one end of acatheter, inserting the end of the catheter through the skin into a bodylumen, advancing the catheter in the body lumen to a desired treatmentlocation, expanding the stent at the treatment location, and removingthe catheter from the lumen. In the case of a balloon expandable stent,the stent is mounted about a balloon disposed on the catheter. Mountingthe stent typically involves compressing or crimping the stent onto theballoon. The stent is then expanded by inflating the balloon. Theballoon may then be deflated and the catheter withdrawn. In the case ofa self-expanding stent, the stent may be secured to the catheter via aretractable sheath or a sock.

When the stent is in a desired bodily location, the sheath may bewithdrawn allowing the stent to self-expand. This requires a sufficientdegree of strength and rigidity or stiffness. In addition to havingadequate radial strength, the stent should be longitudinally flexible toallow it to be maneuvered through a tortuous vascular path.

Thus, a stent is typically composed of a scaffolding that includes apattern or network of interconnecting structural elements or struts. Thescaffolding can be formed of tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed to allow the stent to beradially expandable. The pattern is generally designed to maintain thelongitudinal flexibility and radial rigidity required of the stent.Longitudinal flexibility facilitates delivery of the stent and radialrigidity is needed to hold open a body lumen. A medicated stent may befabricated by coating the surface of either a metallic or polymericscaffolding with a polymeric carrier that includes a bioactive agent.The polymeric scaffolding may also serve as a carrier of bioactiveagent.

In many treatment applications of stents, the presence of a stent in abody may be necessary for a limited period of time until its intendedfunction of, for example, maintaining vascular patency and/or drugdelivery is accomplished. Thus, stents are often fabricated frombiodegradable, bioabsorbable, and/or bioerodable materials such thatthey completely erode only after the clinical need for them has ended.In addition, a stent should also be capable of satisfying the mechanicalrequirements discussed above during the desired treatment time.

A polymeric stent should be mechanically stable throughout the range ofstress experienced during use. In addition to mechanical stability, astent should have a sufficient rate of biodegradability or erosion asdictated by a treatment regimen. However, one of the major clinicalchallenges of bioabsorbable stents is adequately suppressinginflammatory responses triggered by the degradation of the stent. Theembodiments of the invention address this and other concerns.

SUMMARY OF THE INVENTION

Disclosed is a stent comprising a bioabsorbable polymeric scaffolding;and a plurality of depots in at least a portion of the scaffolding,wherein the plurality of depots comprise a bioabsorbable material,wherein the degradation rate of all or substantially all of thebioabsorbable polymer of the scaffolding is faster than the degradationrate of all or substantially all of the bioabsorbable material of thedepots.

Also disclosed is a method treating a body lumen, the method comprisingproviding a stent comprising a scaffolding having a plurality of depots,wherein the scaffolding degrades at a faster rate than a material in theplurality of depots and deploying the stent at a treatment area in abody lumen.

Also disclosed is a method of treating a body lumen, the methodcomprising deploying a first stent at a treatment area, wherein thefirst stent includes a bioabsorbable polymeric scaffolding and aplurality of depots in at least a portion of the scaffolding, whereinthe depots have a bioabsorbable material, and wherein the degradationrate of all or substantially all of the bioabsorbable polymer of thescaffolding is faster than the degradation rate of all or substantiallyall of the bioabsorbable material in the depots and deploying a secondstent in at least a portion of the treatment area.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a stent.

FIG. 2(a) depicts a cross-section of a stent implanted in a body lumen,the stent having a scaffolding and a drug coating.

FIG. 2(b) depicts the stent of FIG. 2(a) after endothelialization of thestent in the body lumen.

FIG. 2(c) depicts the stent of FIG. 2(a) after endothelialization of thestent and degradation of the scaffolding, where the drug coating of thestent remains lodged in the lumen and continues to deliver drug in thelumen.

FIG. 3 depicts a second stent that is implanted at a treatment area of afirst stent, where the scaffolding (not depicted) of the first stent hasdegraded but the coating of the first stent remains lodged in the lumenwall.

FIG. 4(a) depicts a cross section of a stent implanted in a body lumen,the stent having a scaffolding and depots.

FIG. 4(b) depicts the stent of FIG. 4(a) after endothelialization of thestent in the body lumen.

FIG. 4(c) depicts the stent of FIG. 4(a) after endothelialization of thestent and degradation of the scaffolding.

FIG. 5 depicts a second stent that is implanted at a treatment area ofthe first stent, where the scaffolding (not depicted) of the first stenthas degraded.

DETAILED DESCRIPTION

A common disorder associated with mechanical modification of a vessel,such as by a balloon or stenting is restenosis. A number of cellularmechanisms have been proposed that lead to restenosis of a vessel, suchas inflammatory response to injury and foreign body presence.

Inflammation is a defensive, biological response to injury, infection,or an abrupt change in tissue homeostasis. In nature, inflammatoryresponses are designed to destroy, dilute and isolate injurious agentsand then lead to recovery and repair of the affected tissue. Vascularinflammation is the first stage of the inflammatory response, developingafter the initial contact with the stimulus and continuing sometimes forseveral days. The presence of a stimulatory agent in the blood or in thetissue triggers the body's response through endothelial cells. Theendothelial cell layer is the innermost layer of larger vessels and theonly cell layer of the smallest vessels, the capillaries.

Additionally, the presence of a biodegradable foreign body, such as abiodegradable stent in a vessel can lead to or aggravate an inflammatoryresponse, thus leading to more aggressive restenosis.

Biodegradation refers generally to changes in physical and chemicalproperties that occur (e.g., in a polymer) upon exposure to bodilyfluids as in a vascular environment. The changes in properties mayinclude a decrease in molecular weight, deterioration of mechanicalproperties, and decrease in mass due to erosion or absorption. Thedecrease in molecular weight may be caused by chemical reactions ofbodily fluids with the polymer, for example, hydrolysis and/or metabolicprocesses. By-products of such degradation reactions can be responsiblefor inciting inflammation. For example, by-products of hydrolysis areproduced when polymer molecules are cleaved into component parts by theaddition of water. Various by-products of degradation of biodegradablepolymers are known to incite an inflammatory response. For example,lactic acid, a degradation by-product of poly(lactic acid) polymers, isknown to cause an inflammatory response.

Furthermore, the release of by-products into the body from abiodegradable stent occurs continuously from the time of first exposureto bodily fluids to a time when the stent is either completely degradedand eliminated or removed from the body. It follows that throughout thistime frame, the body is continuously exposed to inflammation-incitingby-products. Therefore, it is desirable for the stent to degrade rapidlyonce the need for support of the lumen has expired.

Described herein is a drug-delivery stent that allows delivery of drugeven after the stent scaffolding has degraded. Thus, the stentscaffolding need not remain in the body lumen to deliver drug. The stentscaffolding may be made to degrade rapidly and completely orsubstantially completely disappear once the need for support of thelumen has expired. The drug-delivery stent described herein includes oneor more drugs for treating a vascular disorder or a related disorder.The drugs, for example, can be a combination of at least oneanti-proliferative agent, at least one anti-inflammatory agent, andoptionally other types of bioactive agents.

Embodiments also disclose a method of delivering a drug into a lumen.The method provides for implanting a medical device, such as a stent,that may include depots at a surface of the stent containing a depotmaterial which degrades at a slower rate than a stent scaffolding.Alternatively, or in addition to the depots, the stent may include acoating material above a surface of the stent which degrades at a slowerrate than the scaffolding. The coating and/or depot material is used forcarrying a variety of drugs including but not limited to therapeuticsubstances and polymers impregnated with therapeutic substances. Thedrug from the coating and/or depot material can be released into thelumen after the scaffolding of the stent has degraded.

Certain embodiments provide for a rapidly degrading scaffolding thatdegrades within 6 months, within 3 months, or more narrowly within 2months. Re-stenting is facilitated by rapid degradation of the firststent's scaffolding, enabling a second stent to be implanted in thestented area or treatment area within only a few months after the firststent has been implanted. When the second stent is deployed in thetreatment area, the functional lumen diameter is not reduced as is thecase when a second stent is deployed at a treatment area of a firststent that has only partially degraded or not degraded at all in thecase of a stent made from a non-degradable material. In the latter case,the reduced functional diameter causes the blood flow to fallsignificantly and possibly congest the lumen.

As discussed above, a drug(s) may be included in a coating and/or depotmaterial, of the first stent. Thus, when the second stent is implanted,the first stent may deliver drug from at least a portion of the coatingand/or depot material of the first stent while the second stent isimplanted. For example, an anti-inflammatory agent may be includedwithin the coating and/or depot material of the first stent, such thatwhen the second stent is implanted, the anti-inflammatory agentcontinues to deliver drug to prevent inflammation. In addition, theanti-inflammatory agent that is delivered from the coating and/or depotmaterial of the first stent may also effectively suppress inflammationof a lumen during all or a majority of the degradation of thescaffolding of the first stent.

In a further embodiment, a drug is included in the coating, in aplurality of depots, and/or the scaffolding of the stent, and isdesigned to have release parameters for drugs included. The second stentmay or may not include a coating, a plurality of depots, or a drug. Thesecond stent may have a biostable or biodegradable scaffolding made froma metal, polymer, or combination thereof. The drug mixed or dispersedwithin a biodegradable scaffolding may be delivered into a lumen atsubstantially the same, a faster rate, or a slower rate as thescaffolding degrades. In one embodiment, the drug may be incorporatedwithin the scaffolding during fabrication of the stent according tothose of skill in the art. For example, an anti-inflammatory agent maybe incorporated in the scaffolding, and configured to be deliveredthrough the coating and/or depot material in a plurality of depots totreat inflamed portions of lumen.

Moreover, the properties of the coating and/or depot material, such asthickness and porosity, may influence the rate of release of the drug(s)from the stent. Some embodiments may include controlling the releaserate of the drug by modifying the properties of the coating and/or depotmaterial.

A biodegradable stent can remain in the body and a drug can be deliveredin the body for a duration of time at least until its intended functionof, for example, maintaining vascular patency and drug delivery isaccomplished. Biodegradable polymers are used to form the stent, suchthat the entire stent can be made to disappear after the process ofdegradation, erosion, or absorption. In some embodiments, verynegligible traces of polymer or residue are left behind. The duration istypically in the range of 6-12, 6-18, or 6-24 months, for example. Thetime needed to maintain vascular patency can be shorter than the drugdelivery time.

The term “stent” is intended to include, but is not limited to,self-expandable stents, balloon-expandable stents, stent-grafts, andgrafts. The structure of the stent can be of virtually any design. Astent, for example, may include a pattern or network of interconnectingstructural elements or struts. FIG. 1 depicts an example of athree-dimensional view of a stent 100. The stent may have any patternthat includes a number of interconnecting elements or struts 110. Asdepicted in FIG. 1 the geometry or shape of stents vary throughout itsstructure. In some embodiments, a stent may be formed from a tube bylaser cutting the pattern of struts into the tube. The stent may also beformed by laser cutting a polymeric sheet, rolling the pattern into theshape of the cylindrical stent, and providing a longitudinal weld toform the stent.

FIG. 2(a) depicts a cross section of a stent implanted in a body lumen.A stent 200 according to one embodiment of the invention includes abioabsorbable polymeric scaffolding 210 and a coating material 220 on atleast a portion of the scaffolding 210. Coating material 220 may includea drug and a bioabsorbable polymer. Although coating material 220 isonly depicted in FIGS. 2(a) and 2(b) as being on one of stent 200, itshould be understood by those skilled in the art that stent 200 can alsobe coated on the other side of stent 200. In one embodiment, thedegradation rate of all or substantially all of scaffolding 210 isfaster than the degradation rate of all or substantially all of coatingmaterial 220. Thus, the defined degradation time of all or substantiallyall of scaffolding 210 is shorter than the degradation time of all orsubstantially all coating material 220. By providing a scaffolding 210that has a faster degradation rate than its coating 220, scaffolding 210degrades away or disappears, while coating material 220 continues todeliver drug. In one embodiment, coating material 220 continues todeliver drug after scaffolding 210 has completely degraded. FIG. 2(b)depicts stent 200 after endothelialization of stent 200 in lumen wall240. In one embodiment, all or substantially all of coating material 220degrades faster than all or substantially all of scaffolding 210. Inanother embodiment, coating material 220 continues to elute drugs evenafter scaffolding 210 no longer supports lumen wall 240.

Turning now to FIG. 2(c), with continual reference to FIG. 2(b), coatingmaterial 220 remains lodged in lumen wall 240 after scaffolding 210substantially degrades. Because coating material 220 can be made todeliver drug even after the disintegration of scaffolding 210, theinvention enables stent 200 to release drug for an extended period oftime throughout the life of stent 200 while scaffolding 210 degrades,and if desired, long after scaffolding 210 degrades. In one embodiment,stent 200 delivers drug for over 50% of the life of scaffolding 210. Inanother embodiment, stent 200 delivers drug for over 80% of the life ofscaffolding 210. In yet another embodiment, stent 200 delivers drug forthe entire life of scaffolding 210, or 100% of the life of scaffolding210. Thus, after the entire scaffolding 210 has completely degraded,coating material 220 may be designed to continue to deliver drug, asdepicted in FIG. 2(c).

In one embodiment, upon deployment of stent 200 in a treatment area,scaffolding 210 substantially or completely degrades from the treatmentarea before coating 220 substantially or completely degrades. In anotherembodiment, coating 220 delivers a drug to lumen wall 240 duringdegradation of scaffolding 210 and after substantial or completedegradation of scaffolding 210. In yet another embodiment, coating 220becomes endothelialized in a lumen wall 240 and delivers a drug afterscaffolding 210 has substantially or completely degraded. Depicted inFIG. 3 is a second stent 300 that has been implanted in the sametreatment area 230 as the first stent, where the scaffolding (notdepicted) of the first stent has degraded but coating material 220 offirst stent remains lodged in the lumen wall. In some embodiments,second stent 300 is implanted in lumen wall 240 after endothelializationof first stent. In some embodiments, second stent 300 is implanted inlumen wall 240 after a scaffolding (not depicted) of a first stent is atleast partially degraded, substantially degraded, or more narrowly,completely degraded in lumen wall 240. In some embodiments, second stent300 is deployed in treatment area 230 when scaffolding (not depicted) ofthe first stent is greater than 50% degraded, greater than 75% degraded,and more narrowly, greater than 95% degraded.

In one embodiment, second stent 300 may be implanted in treatment area230 after all or substantially all of scaffolding (not depicted) offirst stent has degraded, such that only a coating material 220 of thefirst stent remains in lumen wall 240. In certain embodiments, coatingmaterial 220 of the first stent continues to deliver drug in lumen wall240 when second stent 300 is implanted.

As mentioned above, second stent 300 is deployed when the scaffolding(not shown) of the first stent has at least partially degraded, hassubstantially degraded, or has completely degraded. Thus, embodimentsdisclosed herein may prove advantageous to methods for “re-stenting” alumen.

In one embodiment, the stent includes depots in the stent scaffoldinghaving depot material such as drug. According to one embodiment of theinvention, one or more drugs or a drug-polymer mixture may be containedwithin at least one depot or cavity at the stent surface in at least aportion of the scaffolding. FIG. 4(a) depicts a cross section of a stent400 having a scaffolding 410 and a plurality of depots filled with depotmaterial 420. Stent 400 is implanted in a treatment site 430 of a lumen440. Like the drug coating discussed above, the degradation rate of atleast a portion of scaffolding 410 is faster than the degradation rateof all or substantially all depot material within the depots.

In one embodiment, the degradation rate of all or substantially all ofscaffolding 410 is faster than the degradation rate of all orsubstantially all of depot material 420 that is within the depots. Thus,the degradation time of all or substantially all scaffolding 410 isshorter than the degradation time of all or substantially all depotmaterial 420. By providing a scaffolding 410 that has a fasterdegradation rate than its depot material 420, scaffolding 410 degradesaway, while depot material 220 in the depots continues to deliver drug.In one embodiment, depot material 420 continues to deliver drug afterscaffolding 410 has completely degraded. FIG. 4(b) depicts stent 400after endothelialization of stent 400 in lumen wall 440. In oneembodiment, all or substantially all of depot material 420 degradesfaster than all or substantially all of scaffolding 410. In anotherembodiment, depot material 420 remains and continues to elute drugs evenafter scaffolding 410 no longer supports lumen wall 440.

Turning now to FIG. 4(c), with continual reference to FIG. 4(b), depotmaterial 420 remains lodged in lumen wall 440 after scaffolding 410substantially degrades. Because depot material 420 can be made todeliver drug even after the disintegration of scaffolding 410, theinvention enables stent 400 to release drug for an extended period oftime throughout the life of stent 400 while scaffolding 410 degrades,and if desired, long after scaffolding 410 degrades. In one embodiment,stent 400 delivers drug for over 50% of the life of scaffolding 410. Inanother embodiment, stent 400 delivers drug for over 80% of the life ofscaffolding 410. In yet another embodiment, stent 400 delivers drug forthe entire life of scaffolding 410, or 100% of the life of scaffolding410. Thus, after the entire scaffolding 410 has completely degraded,depot material 420 may be designed to continue to deliver drug, asdepicted in FIG. 4(c).

In one embodiment, upon deployment of stent 400 in the treatment area,scaffolding 410 substantially or completely degrades from treatment areabefore depot material 420 substantially or completely degrades. Inanother embodiment, depot material 420 delivers a drug to the lumen 440during degradation of scaffolding 410 and after substantial or completedegradation of scaffolding 410. In yet another embodiment, depotmaterial 420 becomes endothelialized in a lumen wall 440 and delivers adrug after the scaffolding has substantially or completely degraded.

Depicted in FIG. 5 is a second stent 500 that has been implanted in thesame treatment area 430 as the first stent 400. In some embodiments,second stent 500 is implanted in the lumen at treatment area 430 afterendothelialization of first stent. As depicted in FIG. 5, depot material420 of first stent remains lodged in lumen 430. In some embodiments,second stent 500 is implanted in lumen 430 after a scaffolding (notdepicted) of a first stent 500 is at least partially degraded,substantially degraded, or more narrowly, completely degraded in lumen430. In some embodiments, second stent 500 is deployed in treatment area410 when scaffolding (not depicted) of the first stent is greater than50% degraded, greater than 75% degraded, and more narrowly, greater than95% degraded as known of those skilled in the art.

In one embodiment, second stent 500 may be implanted in treatment area430 after all or substantially all of scaffolding of first stent hasdegraded, such that only depot material 420 in the depots of first stentremains in the lumen. In certain embodiments, depot material of firststent 400 continues to deliver drug when second stent 500 is implanted.

As discussed above, a drug(s) may be included in depot material 420 ofthe first stent or the scaffolding (not depicted). Thus, when secondstent 500 is implanted, the first stent may deliver drug from at least aportion of depot material 420 of first stent 400 while second stent 500is implanted. For example, an anti-inflammatory agent may be includedwithin depot material 420 of first stent 400, such that when scaffoldingof second stent 500 is implanted, depot material 420 continues todeliver an anti-inflammatory agent to prevent inflammation. As mentionedabove, the anti-inflammatory agent that is delivered from depot material420 of first stent 400 may also effectively suppress inflammation of alumen during all or a majority of the degradation of the scaffolding(not depicted) of first stent 400.

In a further embodiment, an anti-inflammatory drug and/or ananti-proliferative drug is included in the depots and/or the scaffoldingof the stent and is designed to have certain release parameters for thedrugs. Second stent 500 may have a biostable or biodegradablescaffolding made from a metal, polymer, or combination thereof. Secondstent 500 may or may not include a coating, depots, or a drug.

In some embodiments, a coating is deposited over a scaffolding havingdepots. For example, the scaffolding may include a coating that maydegrade at a slower rate than the scaffolding. The coating may beincluded in addition to the slow-degrading depot material. In someembodiments, the depot material, the coating material, and thescaffolding can be fabricated to have different degradation rates. Forexample, the coating material may have the slowest degradation rate,such that the depot material and scaffolding degrade prior to thecoating. Thus, the coating material can be made to elute drugs during orafter degradation of the depots or the scaffolding. The depot materialcould have the same degradation rate as the coating material.Alternatively, the depot material could have a slower degradation rateas the coating.

The depots may be designed in a variety of shapes and depths, dependingon the desired delivery profile of the drug(s). For example, the depotsmay be formed having a cylindrical, a conical, or an inverted-conicalshape. The depots may be formed into the stent by methods known to thoseof skill in the art. Depots may be formed on a body of the stent byexposing a surface of the stent to an energy discharge from a laser,such as an excimer laser. Alternative methods of forming depots include,but are not limited to physical or chemical etching techniques. Depotscan be formed in virtually any stent structure and not merely theabove-described structure.

Numerous embodiments of a stent with depots configured to hold a drugare possible. Depots may be placed at one or more arbitrary locations ona stent. The greater inflammation may arise from a larger concentrationof degradation products closer to the center of the stent than the endsof the stent. Thus, the center of the lesion may require moreanti-inflammatory agent than the ends of the lesion. Alternatively, theends of the lesion may be more inflamed due to mechanical stressescausing irritation or injury to the ends of the lesion. Thus, a stentmay include depots or more depots in regions of a stent adjacentportions of a lesion having more inflammation.

The coating or depot material may include a drug, a cell, a gene, abioactive agent, or other therapeutic substances. In some embodiments,the drug coating or depot material may include a bioactive agent. A“bioactive agent” is a moiety that is mixed, blended, bonded or linkedto a polymer coating or depot material, or to a polymer from which astent scaffolding is made, and provides a therapeutic effect, aprophylactic effect, both a therapeutic and a prophylactic effect, orother biologically active effect upon release from the stent. Thebioactive agents of the present invention may remain linked to a portionof the polymer or be released from the polymer. It should also beunderstood by those skilled in the art that multiple drugs can beincluded in a single depot, multiple depots, or the coating material.The material in the depot can be drug mixed or dispersed in a polymermatrix. The polymer matrix can degrade at a slower rate than thescaffolding. Depot material can be deposited in the depots according tomethods known to those of skill in the art.

In one embodiment, the stent includes an anti-proliferative agent thatincludes, but is not limited to, Everolimus, Rapamycin, and/orderivatives thereof. Everolimus is available under the trade nameCertican™, Novartis Pharma AG, Germany. The anti-proliferative agent maybe included within the coating or depot material and/or in thescaffolding's polymer matrix. In one embodiment, the anti-proliferativeagent is intermixed or dispersed within the coating or depot materialand/or in the scaffolding's polymer matrix. In certain embodiments, theanti-proliferative agent is included in the depot material, within thecoating, and/or within the scaffolding.

The stent may also include an anti-inflammatory agent, such asClobetasol, which is available under the trade name Temovate™,Glaxosmithkline, UK. The anti-inflammatory agent may be included withinthe coating or depot material's polymer matrix and/or in thescaffolding's polymer matrix. In one embodiment, the anti-inflammatoryagent is intermixed or dispersed within the polymer matrix of thecoating or depot material and/or intermixed or dispersed within thescaffolding's polymer matrix. In certain embodiments, theanti-inflammatory agent is included within the depot material and/or thescaffolding.

The release of inflammation-inciting by-products into the body from abiodegradable device can occur continuously while the scaffolding isdegrading within the body. An anti-inflammatory included within thescaffolding may allow for sustained release of the inflammatory agentthroughout the degradation of the scaffolding. The drug-delivery stentdisclosed herein may include a sustained release of an anti-inflammatoryagent from the scaffolding. After the scaffolding absorbs, the coatingor depot material in the lumen wall remains to deliver drug in thelumen.

As discussed above, underlying stent scaffolding may be made from apolymeric material that degrades more rapidly than the polymer used toform the coating or depot material. Any biodegradable polymer may beused to the form the scaffolding and the coating or depot material, aslong as the polymer used to make all or substantially all thescaffolding degrades faster than the polymer used to make all orsubstantially all the coating or depot material. In some embodiments,the scaffolding can be formed of a copolymer that includes twofunctional groups or units. One of the units tends to increase thedegradation rate compared to a homopolymer including the other unit.

In one embodiment, the stent scaffolding is formed of poly(D,L-lactide).In another embodiment, the stent scaffolding is formed ofpoly(D,L-lactide-co-glycolide), where 10% of the copolymer isD,L-lactide and 90% of the copolymer is glycolide. In anotherembodiment, the stent scaffolding is formed ofpoly(L-lactide-co-glycolide), where 10% of the copolymer is D,L-lactideand 90% of the copolymer is glycolide. In this embodiment, any polymerthat degrades at a slower rate than poly(D,L-lactide-co-glycolide) maybe used to form the coating/depot material. For example, poly(L-lactide)(PLLA) can be used to form a coating or depot material because PLLA isslower degrading than poly(D,L-lactide-co-glycolide). In anotherembodiment, the stent scaffolding is formed ofpoly(D,L-lactide-co-glycolide), where 5-45% of the copolymer isD,L-lactide and 55-95% of the copolymer is glycolide. In yet anotherembodiment, 1:1 mixture of Everolimus and poly(D,L-lactide) is used toform the coating or depot material, which completely degrades at about12 months and has the ability to deliver drug for 3 months. Thus, thedrug will be delivered even after the scaffolding has degraded, or hasbeen absorbed into the body, or no longer supports the lumen. In certainembodiments, a scaffolding can be fabricated that degrades within 6months, within 3 months, or more narrowly within 2 months.

Other material may also be used to fabricate the stent scaffolding, solong as all or substantially all of the scaffolding degrades at a fasterrate than all or substantially all of the coating or depot material. Inone embodiment, the coating or depot material includes Everolimus andpoly(D,L-lactide) of a 1:1 ratio, and the scaffolding includesD,L-lactide and glycolide monomers in a 1:9 ratio withpoly(D,L-lactide-co-glycolide).

As described above, it is also possible to have a sustained release ofan anti-inflammatory agent from the coating or depot material. Theanti-inflammatory agent may be included within the coating and/or depotmaterial and is delivered from the coating and/or depots. The coatingand/or depot material may be configured to sustain delivery ofanti-inflammatory agent throughout the degradation of a stentscaffolding to counteract the inflammatory effect of the degradation ofby-products of the scaffolding.

In one embodiment, an anti-inflammatory agent is included in both thecoating material and the scaffolding. In another embodiment, ananti-inflammatory agent is included in both the depot material and thescaffolding. In another embodiment, an anti-inflammatory agent isincluded in the coating, depot material, and the scaffolding. Thus, ananti-inflammatory agent may be delivered from the coating, depots,and/or the scaffolding to suppress inflammation of a body lumen duringall or a majority of the degradation of the scaffolding.

Any drugs having anti-inflammatory effects can be used in the presentinvention. The anti-inflammatory drug can be a steroidalanti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, Clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, deflazacort, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

The anti-proliferative agent can be a natural proteineous agent such asa cytotoxin or a synthetic molecule. Preferably, the active agentsinclude antiproliferative substances such as actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck) (synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁), all taxoids such astaxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimusdrugs such as macrolide antibiotics, rapamycin, Everolimus, structuralderivatives and functional analogues of rapamycin, structuralderivatives and functional analogues of Everolimus, FKBP-12 mediatedmTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugsthereof, and combinations thereof. Representative rapamycin derivativesinclude 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by AbbotLaboratories, Abbot Park, Ill.), prodrugs thereof, co-drugs thereof, andcombinations thereof.

The relative amount of the anti-proliferative agent and/oranti-inflammatory agent in the stent can be determined by the lumen tobe treated. For example, where Everolimus is used as theanti-proliferative agent and Clobetasol is used as the anti-inflammatoryagent, the relative amount of Everolimus and Clobetasol can be variedfor different types of lesions, that is, the relative amount ofEverolimus can be higher for more proliferative lesions, and on theother hand, the relative amount of Clobetasol can be higher for moreinflammatory lesions.

In some embodiments, other agents can be used in combination with theanti-proliferative agent and the anti-inflammatory agents. Thesebioactive agents can be any agent which is a therapeutic, prophylactic,or diagnostic agent. These agents can also have anti-proliferativeand/or anti-inflammatory properties or can have other properties such asantineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant aswell as cystostatic agents. Examples of suitable therapeutic andprophylactic agents include synthetic inorganic and organic compounds,proteins and peptides, polysaccharides and other sugars, lipids, and DNAand RNA nucleic acid sequences having therapeutic, prophylactic ordiagnostic activities. Nucleic acid sequences include genes, antisensemolecules which bind to complementary DNA to inhibit transcription, andribozymes. Some other examples of other bioactive agents includeantibodies, receptor ligands, enzymes, adhesion peptides, blood clottingfactors, inhibitors or clot dissolving agents such as streptokinase andtissue plasminogen activator, antigens for immunization, hormones andgrowth factors, oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax ä (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of such cytostatic substance includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford,Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® fromMerck & Co., Inc., Whitehouse Station, N.J.). An example of anantiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,and genetically engineered epithelial cells. The foregoing substancesare listed by way of example and are not meant to be limiting. Otheractive agents which are currently available or that may be developed inthe future are equally applicable.

Representative examples of polymers that may be used to fabricate thescaffolding, the coating material, and the depot material, or to providea drug delivery particle with the anti-proliferative drug and/oranti-inflammatory drug include, but are not limited topoly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide);poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyethylene amide, polyethylene acrylate, poly(glycolicacid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (such as polyvinyl chloride),polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidenehalides (such as polyvinylidene chloride), polyacrylonitrile, polyvinylketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters(such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABSresins, polyamides (such as Nylon 66 and polycaprolactam),polycarbonates, polyoxymethylenes, polyimides, polyethers,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose.

Additional representative examples of polymers that may be especiallysuited for use in fabricating the scaffolding, the coating material, andthe depot material according to the methods disclosed herein includeethylene vinyl alcohol copolymer (commonly known by the generic nameEVOH or by the trade name EVAL), poly(butyl methacrylate),poly(vinylidene fluoride-co-hexafluororpropene) (e.g., SOLEF 21508,available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidenefluoride (otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

In some embodiments, scaffolding material can also be fabricated fromerodible metals. Metals may be biostable or bioerodible. Some metals areconsidered bioerodible since they tend to erode or corrode relativelyrapidly when implanted or when exposed to bodily fluids. Biostablemetals refer to metals that are not bioerodible. Biostable metals havenegligible erosion or corrosion rates when implanted or when exposed tobodily fluids. Representative examples of biodegradable metals that maybe used to fabricate a stent include, but are not limited to, magnesium,zinc, and iron.

A coating can be formed on a stent or depot material deposited in depotsin a stent using spraying, dipping, or other methods known in the art.In such methods, the components of the coating or depot material aredissolved or suspended in a fluid to form a coating solution. Forexample, a polymer is dissolved in a suitable solvent and a drug isdissolved or suspended in the solvent. The coating solution is thenapplied to the stent. The solvent is then removed, leaving a coating ordepot material within depots. “Solvent” is defined as a substancecapable of dissolving or dispersing one or more other substances orcapable of at least partially dissolving or dispersing the substance(s)to form a uniformly dispersed solution at the molecular- or ionic-sizelevel. The solvent should be capable of dissolving at least 0.1 mg ofthe polymer in 1 ml of the solvent, and more narrowly 0.5 mg in 1 ml atambient temperature and ambient pressure.

In some embodiments, a coating can include a primer layer and/or topcoatlayer. The primer is beneath a drug/therapeutic substance layer and thetopcoat layer above it. A topcoat layer can also be included overdepots. Both the primer layer and the topcoat layer can be without anydrugs/therapeutic substances. In some embodiments, some drug mayincidentally migrate into the primer layer or region. The primer layerimproves adhesion of the drug layer to the stent surface. The topcoatlayer reduces the rate of release of the drug from the coating and/ordepots and/or provides for bio-beneficial properties.

Although embodiments disclosed herein are focused on stents, theembodiments may be applied to any implantable medical device having acoating and/or depots on a substrate. The stent or drug-delivery systemdisclosed herein can be used to treat or prevent a disorder includingbut not limited to thrombosis, high cholesterol, hemorrhage, vasculardissection or perforation, vascular aneurysm, vulnerable plaque, chronictotal occlusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, restenosis and progression of atherosclerosis in patientsubsets including type I diabetics, type II diabetics, metabolicsyndrome and syndrome X, vulnerable lesions including those withthin-capped fibroatheromatous lesions, systemic infections includinggingivitis, hellobacteria, and cytomegalovirus, and combinationsthereof.

A stent having the above-described coating or depot material is usefulfor a variety of medical procedures, including, by way of example,treatment of obstructions caused by tumors in bile ducts, esophagus,trachea/bronchi and other biological passageways. A stent having theabove-described coating material is particularly useful for treatingoccluded regions of body lumens caused by abnormal or inappropriatemigration and proliferation of smooth muscle cells, thrombosis, andrestenosis. Stents may be placed in a wide array of body lumens, botharteries and veins. Representative examples of sites include the iliac,renal, and coronary arteries.

While particular embodiments of the present invention have been depictedand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

What is claimed is:
 1. A method of treating a body lumen, the methodcomprising: providing a stent comprising a scaffolding having aplurality of depots and each filled with a depot material, wherein thescaffolding degrades at a faster rate than the depot material; anddeploying the stent at a treatment area in a body lumen, wherein upondeployment, the stent becomes endothelialized within a wall of the lumenand after a degradation time of the scaffolding, the scaffoldingcompletely absorbs away leaving the depot material lodged within a wallof the lumen at a plurality of locations of the depots, and whereinafter a degradation time of the depot material, the depot material leftlodged within the wall of the lumen completely absorbs away from withinthe wall of the lumen.
 2. The method according to claim 1, wherein thestent includes an anti-proliferative agent, an anti-inflammatory agent,or a mixture thereof.
 3. The method according to claim 1, wherein ananti-inflammatory agent is mixed or dispersed within the scaffolding. 4.The method according to claim 1, wherein an anti-inflammatory agent andan anti-proliferative agent is delivered from at least a portion of thedepots.
 5. The method according to claim 1, wherein an anti-inflammatoryagent is delivered from the scaffolding and suppresses inflammation ofthe lumen during all or a majority of the absorption of the scaffolding.6. The method according to claim 1, wherein the depot material deliversa drug to the lumen during absorption of the scaffolding and aftersubstantial or complete absorption of the scaffolding.
 7. The methodaccording to claim 1, wherein the depot material lodged in the wall ofthe lumen delivers a drug after the scaffolding has substantially orcompletely absorbed.
 8. The method according to claim 1, wherein thescaffolding comprises a bioabsorbable polymer and the depot materialcomprises a mixture of a drug and a bioabsorbable polymer.